2-substituted-p-nitro-anilines

ABSTRACT

NOVEL 2-SUBSTITUTED-P-NITRO ANILINES AND A METHOD FOR THEIR PREPARATION ARE DISCLOSED. THESE COMPOUNDS ARE USEFUL AS INTERMEDIATES IN THE PREPARATION OF PHARMACOLOGICALLY USEFUL 2,3-HIHYDRO-3-(N-SUBSTITUTED CARBAMOYL)7-NITRO-1,4-BENZODIAZEPHINES.

United States Patent Ofice 3,707,473 Patented Dec. 26, 1972 US. Cl.260-293;.76 Claims ABSTRACT OF THE DISCLOSURE Novel2-substituted-p-nitro-anilines and a method for their preparation aredisclosed. These compounds are useful as intermediates in thepreparation of pharmacologically useful 2,3-dihydro3-(N-substitutedcarbamoy1)- 7-nitro-1,4-benzodiazepines.

CROSS REFERENCES TO RELATED APPLICATIONS This application is adivisional application of US. patent application Ser. No. 629,921 filedApr. 11, 1967, and now US. 3,562,251.

SUMMARY OF THE INVENTION This invention is directed to novel2,3-dihydro-1,4-benzodiazepine derivatives and a method for theirpreparation. More particularly, this invention relates to2,3-dihydro-7-nitro-1,4-benzodiazepine derivatives which have anN-substituted carbamoyl group in the 3-position, a method for preparingthese benzodiazepine derivatives and intermediates used in theirpreparation.

DETAILED DESCRIPTION OF THE INVENTION The novel2,3-dihydro-l,4-benzodiazepine derivatives of this invention arecompounds of the formula:

wherein A is selected from the group consisting of C=N and -CH-NH R isselected from the group consisting of hydrogen, lower alkyl, hydroxy andthe group R is selected from the group consisting of lower alkyl andhydrogen; and R and R taken together with their attached nitrogen atomform a five or six membered heterocyclic ring;

R is selected from the group consisting of phenyl, lower alkylsubstituted phenyl, halo substituted phenyl and py y R and R areselected from the group consisting of hydrogen and lower alkyl and R andR taken together form lower alkylidene and their pharmaceuticallyacceptable salts.

The compounds of Formula I above form pharmaceutically acceptable acidaddition salts with both inorganic and organic pharmaceuticallyacceptable acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, citric acid, acetic acid, succinic acid, maleicacid, methane sulfonic acid, p-toluene-sulfonic acid and the like. Suchacid addition salts are also within the scope of the invention.

The compounds of Formula I above can be prepared from2,3-dihydro-1,4-benzodiazepin-2-one compounds of the formula:

i NH-il /CH3 N02 wherein A is as above, by first treating the compoundof Formula II above with an amino compound of the formula:

wherein R and R are as above, to split the1,2-dihydro-1,4-benzodiazepin-2-one ring between the nitrogen at thel-position and the carbonyl group at the 2-position, forming atransamidated product of the formula:

(III) wherein R and R are as above, and A is as above.

The transamidated product is then reacted with a formylating agent toform a compound of the formula:

R1 I1 e x N0 -A-0Hi-i JN R2 wherein A, R and R are as above and R is Ris hydrogen and R and R being taken together to form 0 =CH-N-R and R ishydrogen or lower alkyl and R and R are lower alkyl.

The formulated product is then cyclized to produce a 3 (N substitutedcarbamoyl)-l,4-benzodiazepine of the formula:

The compound of Formula VI above is converted to the compound of FormulaI by treating the compound of Formula VI above with sodium borohydrideor any conventional reducing agent.

The compounds of Formula I above, are useful as anticonvulsants. Thecompounds of Formula I above, as well as their pharmaceuticallyacceptable acid addition salts are used in the form of conventionalpharmaceutical preparations which contain said compounds in connectionwith conventional pharmaceutical organic or inorganic carrier materialssuitable for internal administration. The pharmaceutical compositionscontaining the compounds of Formula I above as well as theirpharmaceutically acceptable acid addition salts, can be administeredparenterally or orally, dosages can be adjusted to individualrequirements, for example these compounds can be administered in dosagesof from about 0.1 mg./kg. to about 10.0 mg./kg. per day. These dosagescan be administered in single dosage form or in divided dosage forms.The pharmaceutical compositions can contain such conventional organic orinorganic inert carrier materials such as water, gelatin, lactose,starch, magnesium stearate, talc, vegetable oils, gums, polyalkyleneglycose, Vaseline or the like. The pharmaceutical preparations can be inthe conventional solid forms such as tablets, dragees, suppositories,capsules or in conventional liquid form such as solutions, suspensionsor emulsions. The pharmaceutical compositions can be submitted toconventional pharmaceutical expedients such as sterilization and/or cancontain conventional pharmaceutical additives such as preservatives,stabilizing agents, wetting agents, emulsifying agents, salts foradjusting the osmotic pressure, buffers or the like. They can alsocontain other therapeutically useful materials.

As used throughout the specification, the term lower alkyl includes bothstraight and branched chain alkyl groups having from 1 to 7 carbon atomssuch as methyl, ethyl, propyl, isopropyl and the like. The term loweralkylidene includes both straight and branched chain alkylidene groupshaving from 1 to 7 carbon atoms such as methylidene, ethylidene,isopropylidene, etc. The term halogen includes all four halogens, i.e.,iodine, bromine, chlorine and fluorine, with chlorine, fluorine andbromine being the preferred halogens.

The preferred 2,3-dihydro-1,4-benzodiazepin-2-ones of Formula II abovewhich are utilized as the starting material in the reactions of thisinvention are those 2,3-dihydro-l,4-benzodiazepin-2-ones wherein R iseither phenyl, 2-pyridyl or phenyl-substituted on the 2-position with ahalo group such as chlorine or fluorine.

The 1,2 dihydro 1,4-benzodiazepin-2-one compounds of Formula II above,are converted to the transamidated products of Formula IV above bytreating the compounds of Formula II with an amino compound of FormulaIII above. This reaction can be carried out at room temperature.However, it is preferred to carry out this reaction at elevatedtemperatures either using the amino compound as solvent or in thepresence of an inert organic solvent. Any conventional inert organicsolvent can be utilized in carrying out this reaction. Typical inertorganic solvents which can be utilized in accordance with this inventioninclude diethyl ether, tetrahydrofuran, benzene, hexane, pentane, ethylpropyl ether and mixtures thereof. However, the preferred organicsolvents are dimethylformamide and dimethylsulfoxide. In carrying outthis reaction, it is generally preferred to utilize temperatures of fromabout C. to about 175 C.

By means of this reaction, the ring of the1,2-dihydrol,4-benzodiazepin-2-one or Formula II above is split at the1-2 position so that transamidation occurs to produce the compounds ofFormula IV above. This reaction is completely unexpected since it hasbeen found that no substantial splitting with the resultanttransamidation occurs if the 2,3-dihydro-1,4-benzodiazepin-2-one whichis utilized as a starting material contains functional groups other thannitro at the 7-position. Hence, it has been discovered that when7-nitro-2,3-dihydro-1,4-benzodiazepin- 2-one is reacted with an aminocompound having at least one reactive hydrogen, splitting of thebenzodiazepin-2- one ring occurs at the l-2 position with the resultanttransamidation.

The preferred organic amino compounds of Formula III above which areutilized in carrying out this reaction are ammonia; primary amines suchas methyl amine, ethylamine, isopropyl amine, propyl amine, butyl amine,etc.; hydrazine and lower alkyl substituted hydrazines such as methylhydrazine, ethyl hydrazine, isopropyl hydrazine; and secondary amines.Among the preferred secondary amines which can be utilized in accordancewith this invention such as the lower alkyl amines which include-diethylamine, dimethyl amine, N,N-propyl butyl amine, N,N-methylethyl amine,etc. and the heterocyclic amines such as pyrrolidine and piperidine.

The transamidated compound of Formula IV above is converted to thecompound of Formula V above by means of reacting the compound of FormulaIV above with a formylating agent. In carrying out this reaction, anyconventional formylating agent can be utilized to formylate the primaryamino group in the compound of Formula IV above. Among the formylatingagents that are utilized in accordance with this invention are formicanhydride, which is formed by placing formic acid in acetic anhydride,mono or di-lower alkyl substituted amides of formic acid or an acetal offormic amide. Typical formylating agents include dimethylformamideacetal, dimethylformamide with thionyl chloride, and formic anhydride.Generally, it is preferred to carry out this reaction using theformylating agent as the solvent or in the presence of an inert organicsolvent. In carrying out this reaction, it is best not to exceed atemperature of over 40 C. since the formation of undesirable by-productsoccurs at high temperatures. Furthermore, it is generally preferred toutilize temperatures from about 10 C. to about 40 C. Any of theconventional inert organic solvents such as those hereinbefore mentionedcan be utilized in carrying out this reaction.

In cyclizing the formylated compound of Formula V above to form the3-(N-substituted carbamoyl)-l,4-benzodiazepine of Formula VI above, thecompound of Formu la V above is heated in the presence of an inertorganic solvent. In carrying out this cyclization reaction, temperaturesof from about 65 C. to 130 C. should be utilized. This cyclizationreaction can be carried out in an inert organic solvent such as any ofthe hereinbefore mentioned organic solvents. The preferred solvents forutilization in this cyclization reaction are xylene, toluene andbenzene.

The 3 (N-substituted carbamoyl)-1,4-benzodiazepines of Formula VI abovecan be converted to the 2,3-dihydro- 3-(N-substitutedcarbamoyl)-l,4-benzodiazepines of Formula I above by means of treatingthe compounds of Formula VI above with sodium borohydride or otherconventional reducing agents in the presence of an inert organicsolvent. Any of the aforementioned inert organic solvents can beutilized in carrying out this reaction. Generally, it is preferred touse ethanol, chloroform or mixtures thereof in carrying out thisreaction. In carrying out this reaction, temperature and pressure arenot critical and the reaction can be carried out at room temperature orelevated temperatures. Generally, it is preferred to utilizetemperatures ranging from 70 C. to the reflux temperature of thesolvents.

The following examples are illustrative but not limitative of thepresent invention. In the examples, the temperature is given in degreescentigrade and the ether utilized was diethyl ether.

EXAMPLE 1 This example is directed to the preparation of2,3-dihydro-3-(N-methyl)carbamoyl-7-nitro 5 phenyl- 1H-1,4-benzodiazepine.

(A) Transamidation A stream of methylamine gas was bubbled into asolution of 10 g. of 1,3 dihydro-7-nitro-2H-1,4-benzodiazepin-Z-one inml. of N,N-dimethylformamide at room temperature. After 30 min. theaddition of methylamine was stopped and the reaction mixture was allowedto stand overnight. Solvent was removed under reduced pressure and theresidue was treated first with 10 ml. of methanol and then with 100 ml.of ether. The product was filtered and recrystallized from ethanol togive 2-[(Z- amino-S-nitrophenyl)phenylmethylenimino] N methylacctamide.

(B) Formylation A flask fitted with a stirrer and dropping funnel wasexternally cooled with an ice bath. 94 percent formic acid (13.6 ml.)was added and cooled (-5 Acetic anhydride (32.8 ml.) was added dropwiseand after the addition was complete the reaction mixture was warmed to50 and maintained at that temperature for 2 hrs. The solution was nextcooled to 0 and 15 g. of 2-[(2-amino-5- nitrophenyl)phenylmethylenimino]N methylacetamide was added with stirring.

The mixture was allowed to warm to room temperature, stirred for 2 hrs.and then poured into 500 ml. of water. The aqueous mixture was madebasic with ammonium hydroxide and filtered. The precipitate was washedwith water then with ethanol and finally with ether to give 2-[(2-formamido nitrophenyl)phenylmethylenimino]- N-methylacetamide aspale yellow rods.

(C) Cyclization A solution of 1 g. of 2-[(2-formamido-5-nitrophenyl)phenylmethylenimino]-N-methylacetamide in 50 ml. of dry toluene washeated under reflux for 7 hrs. Solvents were evaporated and the residuewas crystallized from a mixture of methanol and ether to giveN-methyl-7-nitro- S-phenyl-lH-1,4-benzodiazepine-3-carboxamide.

(D) Reduction A mixture of 3.7 g. (0.0114 In.) of N-methyl-7-nitro- 5phenyl-lH-l,4benzodiazepine-3-carboxamide 3.46 g. (0.09 m.) of sodiumborohydride, 50 ml. of chloroform and 200 ml. of absolute ethanol washeated under reflux for 13 hrs. Water (200 ml.) was added and themixture was filtered. The precipitate was triturated with water anddichloromethane and filtered. A precipitate was retained. The filtratewas placed in a separatory funnel and the layers were separated. Theorganic layer was washed, dried and evaporated to give crude product.The original filtrates were extracted with dichloromethane. The organiclayer was combined, washed, dried and evaporated to give a residue.Recrystallization of this residue from methanol gave crude product. Thethree fractions of crude product were slurried in 50 ml. of ethanoldissolved in 250 ml. of 3 N hydrochloric acid, which was then made basicwith ammonium hydroxide and filtered. Recrystallization of the residuefrom a mixture of chloroform and ethanol gave2,3-dihydro-3-(N-methyl)carbamoyl-7-nitro-5-phenyl-1H-l,4-benzodiazepine.

EXAMPLE 2 This example is directed to the preparation of2,3-dihydro-3-(N-rnethyl)carbamoyl-7-nitro 5 phenyl 1H-l,4-benzodiazepine according to another embodiment of this invention.

(A) Formylation A solution of 70 g. of2-[(2-amino-5-nitrophenyl)phenylmethylenimino]-N-methylacetamide in 375ml. of -N,N- dimethylformamide acetal was stirred at room temperaturefor 6 days. The precipitated product was obtained by filtration and waswashed with ether to give 2-[(dimethylaminomethylenimino 5nitrophenyl)phenylmethyleneimino] -N-methylacetamide as yellow prisms.

(B) Cyclization A solution of 57 g. of 2[(dimethylaminomethylenimino-S-nitrophenyl)phenylmethyleneimino] Nmethylacetamide in 500 ml. of toluene was heated under reflux for 72hrs., cooled slightly and filtered. The precipitate, was washed withether and dried to give N-methyl- 7-nitro-5-phenyl-1H-1,4-benzodiazepine3 carboxamide as dark red prisms.

6 (C) Reduction A mixture of 3.7 g. (0.0114 In.) of N-methyl-7-nitro- 5phenyl-lH-l,4-benzodiazepine-3-carboxamide 3.46 g. (0.09 m.) of sodiumborohydride, 50 ml. of chloroform and 200 ml. of absolute ethanol washeated under reflux for 13 hrs. Water (200 ml.) was added and themixture was filtered. The precipitate was triturated with water anddichloromethane and filtered. A precipitate Was retained. The filtratewas placed in a separatory funnel and the layers were separated. Theorganic layer was washed, dried and evaporated to give crude product.The original filtrates were extracted with dichloromethane. The organiclayer was combined, washed, dried and evaporated to give a residue.Recrystallization of this residue from methanol gave crude product. Thethree fractions of crude product were slurried in 50 m1. of ethanoldissolved in 250 ml. of 3 N hydrochloric acid, which was then made basicwtih ammonium hydroxide and filtered. Recrystallization of the residuefrom a mixture of chloroform and ethanol gave, 2,3-dihydro 3(N-methyl)carbamoyl-7- nitro-S-phenyllH-l ,4-benzodiazepine.

EXAMPLE 3 This example is directed to the preparation of 1-{2- [(2amino-S-nitrophenyl)phenylmethylenimino]acetyl} pyrrolidine.

A solution of 10 g. of l,3-dihydro-7-nitro-5-phenyl-2H1,4-benzodiazepin-2-one in 50 ml. of pyrrolidine was heated under refluxfor 1 hr. The mixture was cooled and filtered to give 1 {2 [(2 amino 5nitrophenyl) phenylmethylenimino]acetyl}pyrrolidine as bright yellowprisms. Recrystallization from 2-ethoxyethanol gave the pure material.

:1 {2 [(2 amino 5 nitrophenyl)phenylmethylenimino]acetyl}pyrrolidine wasformylated, cyclized and reduced by the same process given in parts B,C, and D of Example 1 to give 2,3-dihydro-3-pyrrolidinyl carbonyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine.

EXAMPLE 4 This example is directed to the preparation of 2-[(2 amino 5nitrophenyl)phenylmethylenimino] -N butylacetamide.

A solution of 10 g. of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one in 50 ml. of n-butylamine was heated underreflux for 2 hrs. The solution was evaporated under reduced pressure andthe residue was crystallized from methanol to give2-[(2-amino-5-nitrophenyl) phenylmethylenimino] -N butylacetamide asyellow prisms.

2-[(2 amino 5 nitrophenyl)phenylmethylenimino] N-butylacetamide wasformylated, cyclized and reduced by the same process given in parts B,C, and D of Example 1 to give 2,3-dihydro-3( N-butyl)carbamoyl-7-nitro-S-phenyl-lH-l,4-benzodiazepine.

EXAMPLE 5 (A) Preparation of l-{2-[(Z-amino-S-nitrophenyl)-(2-chlorophenyl)methylenimino]acetyl}piperidine A solution of 9.5 g. of5-(2-chlorophenyl)1,3-dihydro-7-nitro-5-phenyl-2H-l,4-benzodiazepin-2-one in 50 ml. of piperidine washeated under reflux for 1 hr. The solution was poured into 1 l. of waterwhich was then made acidic (pH 4) with hydrochloric acid. The mixturewas extracted with dichloromethane (3X 150 ml.). The organic layers werecombined, washed with 1 N hydrochloric acid (l ml.), water (3x 100 ml.),brine (1X 100 ml.), dried over anhydrous sodium sulfate, filtered andevaporated. Recrystallization of the residue from ethanol gave 1 {2 [(2amino 5 nitrophenyl)- (2-chlorophenyl)methylenimino] acetyl}piperidineas pale yellow prisms.

(B) Preparation of 1{2-[ 2-acetamido-5-nitrophenyl) (2- chlorophenyl-methylen.imin] acetyl}piperidine A mixture of 1 g. of1-{2-[(2-amino-5-nitrophenyl)-(Z-chlorophenyl)methylenimino]acetyl}piperidine; 25 ml. of aceticanhydride and 2.5 g. of sodium acetate was heated on the steam bath for1 hr. and then allowed to stand at room temperature for 2 days. Themixture was poured into ice and water (300 ml.) which was made basic (NHOH) and the product was extracted into dichloromethane (3X 50 ml.). Theorganic layers were combined, washed with water, dried, filtered andevaporated. Recrystallization of the residue from a mixture of benzeneand hexane gave 1{2-[ (2 acetamido 5 nitrophenyl) (2 chlorophenyl)methylenimino1acetyl} piperidine.

l {2 [(2 amino 5 nitrophenyl) (2chlorophenyl)methylenimino]acetyl}piperidine was cyclized and reduced bythe same process as given in parts C and D of Example 1 to give2,3-dihydro-3-piperidine-carbonyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine.

EXAMPLE 6 (A) Preparation of 1-{2-[(2-aminophenyl-S-nitrophenyl)phenylmethylenimino] acetyl} piperidine A solution of g. of1,3-dihydro-7-nitro-2H-l,4- benzodiazepin-Z-one in 50 ml. of piperidinewas heated under reflux for 1 hr. A total of 35 ml. of piperidine wasremoved by distillation and the residue was poured into 50 m1. ofmethanol. The solution was cooled and the product collected byfiltration. Recrystallization of the product from a mixture ofchloroform and ethanol gave 1 {2 [(2 aminophenyl 5nitrophenyDphenylmethylimino] acetyl}piperidine as yellow prisms.

(B) Preparation of 1-{2-[(Z-acetamido-S-nitrophenyl)phenylmethylenimino] acetyl piperidine A mixture of 5 g. ofl-{2-[(2-aminophenyl- 5-nitrophenyl)phenylmethylenimino]acetyl}piperidine, 25 ml. of aceticanhydride and 2.5 g. of sodium acetate was warmed on a steam bath for 3hrs. and then allowed to stand at room temperature for 2 days. Thereaction mixture was poured into a mixture of ice and water which wasthen made basic with ammonium hydroxide. The mixture was extracted withdichloromethane (3X 100 ml.). The organic layers were combined, washedwith water (3X 50 ml.), brine (1x 100 ml.), dried over anhydrous sodiumsulfate, filtered and evaporated. The residue was recrystallized from amixture of benzene and hexane to give 1-{2- [(2 acetamido 5nitrophenyl)phenylmethylenimino] acetyl}piperidine as pale yellowprisms.

1 {2 [(2 acetamido 5 nitrophenyl)phenylmethylenimino]acetyl}piperidinewas cyclized and reduced by the same process given in parts C and D ofExample 1 to give 2,3 dihydro 2 methyl-3-piperidino-carbonyl-7-nitro-S-phenyl-lI-I-1,4-benzodiazepine.

EXAMPLE 7 (A) Transamidation To a stirred mixture of 26.5 g. (0.1 mole)of 1,3-dihydro 7 nitro-S-phenyl-ZH-1,4-benzodiazepin-2-one and 250 ml.of ethanol, 100 ml. of hydrazine hydrate was added at room temperature.The solid dissolved with evolution of heat giving a yellow solution andthe immediate formation of a crystalline yellow compound.Recrystallization from DMF/H O gaveN-(Z-amino-S-nitroa-phenylbenzylidene) glycine hydrazide.

(B) Acylation of the hydrazide A solution of 7.0 g. (22.4 mole) ofN-(Z-amino-S-nitro a phenylbenzylidene)glycine isopropylidene hydrazidewas dissolved in 100 ml. of acetone and allowed to reflux 48 hr. Uponcooling, 0.9 g. of starting material was removed by filtration and thesolvent Was removed from the filtrate giving a crude solid.Recrystallization from gaveN-(2-amino-S-nItro-a-phenylbenisopropylidenehydrazide as yellowacetone-hexane zylidene)-glycine prisms.

N- Z-amino-S-nitro-a-phenylbenzylidene -glycine isopropylidenehydrazidewas formylated cyclized and reduced by the same process given in partsB, C, and D of Example 1 to give2,3-dihydro-7-nitro-1H-1,4-benzodiazepine-3-carboxylicacid-N-Z-isopropylidene hydrazide.

EXAMPLE 8 EXAMPLE 9 A mixture of 26.5 g. 0.1 mole) of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one and 0.5 mole of hydroxylarninein 500 ml. of ethanol was stirred 48 hrs. at room temperature.Filtration afforded pale yellow solid 2 (2amino-S-nitro-a-phenylbenzylideneimino) acetohydroxamic acid.

2 (2 amino 5 nitro oz phenylbenzylideneimino) acetohydroxamic acid wasformylated, cyclized and reduced by the same process given in parts B,C, and D of Example 1 to give 2,3-dihydro-3-hydroxamic acid-7-nitro-5-phenyl-1H-l,4-benzodiazepine.

EXAMPLE 10 This example is directed to the preparation of 2-[1-(2- amino5 nitrophenyl) 1 phenylmethylene imino] acetamide.

A mixture of 10 g. of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one, ml. of conc. ammonium hydroxide and 250 ml. ofN,N-dimethyl-f0rmamide was stored in a closed flask at room temperaturefor 24 hours. The mixture was distilled under reduced pressure and theresidue treated twice with 70 ml. of benzene and the solvent distilledeach time. The yellowish solid thus obtained was resuspended in ml. ofbenzene and filtered to give2-[1-(2-amino-5-nitro-phenyl)-1-phenylmethylene imino]acetamide.

2 [1 (2 amino 5 nitrophenyl) 1 phenylmethylene imino]acetamide wasformylated, cyclized and reduced in the same procedure given in parts B,C and D of Example 1 to give 2,3-dihydro-3-carbamoyl-7-nitro-5-phenyl-lI-I-1,4-benzodiazepine.

'EXAMPLE 11 This example is directed to the preparation of 2-[(2- aminoS-nitrophenyl) (2-chlorophenyl)methyleneimino] acetamide.

A mixture of 35 g. of 5-(2-chlorophenyl)1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one, 300 ml. of conc. ammoniumhydroxide and 1 liter of N,N-dimethylformamide was stored in a closedflask at room temperature for 24 hours. The mixture was distilled underreduced pressure and the residue treated twice with ml. of benzene andthe solvent distilled each time. The yellowish solid thus obtained wasresuspended in 250 ml. of benzene and filtered to give2-[(2-amino-5-nitrophenyl) (2-chlorophenyl)methyleneimino]acetamide.

2 [(2 amino 5 nitrophenyl)(2 chlorophenyl) methyleneimino1acetamide wasformylated, cyclized and reduced in the same manner given in parts B, C,and D of Example 1 to give 2,3-dihydro-3-carbamoyl-7-nitro-5-(2-chlorophenyl)-1H-1,4-benzodiazepine.

EXAMPLE 12 A tablet formulation was prepared containing the followingingredients:

Ingredient: Amount per tablet, mg.

2,3 dihydro 3-(N-methy1)carbamoyl-7-nitro- The procedure in preparing a200 mg. tablet was as follows:

2,3 dihydro 3 (N methyl)carbamoyl 7 nitrophenyl 1H 1,4 benzodiazepine,lactose, corn starch and pregelatinized starch were mixed in a suitablemixer. The mix was passed through a Fitzpatrick Comminuting Machinefitted with No. 1A screen and with knives forward. The mixture wasreturned to the mixer and moistened with water to a thick paste. Themoisture was passed through a No. 12 screen, and the moist granules weredried on paper lined trays at 110 F. The dried granules were returned tothe mixer, and the calcium stearate was added and mixed well. Thegranules were compressed at a tablet weighing 200 mg. using standardconcave punches having a diameter of A EXAMPLE 13 A tablet was preparedcontaining the following ingredients:

Ingredient: Amount per tablet, mg.

2,3 dihydro-3-(N methyl)carbamoyl 7- nitroS-phenyl-1H-1,4-benzodiazepine 25.00 Lactose, U.S.P. 64.50 Corn starch10.00 Magnesium stearate 0.50

The procedure employed in preparing a single tablet was as follows:

2,3 dihydro 3 (N methyl)carbamoyl-7-nitro-5-phenyl-lH-1,4-benzodiazepine was mixed with lactose, corn starch andmagnesium stearate in a suitable mixer. The mixture was further blendedby passing through a Fitzpatrick Comminuting Machine fitted with a No.1A screen with knives forward. The mixed powders were slugged on atablet compressing machine. The slugs were comminuted to a suitable meshsize (No. 16 screen) and mixed well. The tablets were compressed at atablet weight of 100 mg. using tablet punches having a diameter ofapproximately A.

EXAMPLE 14 A 320 mg. tablet was prepared containing the followingingredients:

Amount per Ingredient: tablet, mg.

2,3-dihydro 3 (N-methyl)carbamoyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine 100 Dicalcium phosphate 60 Corn starch157 Magnesium stearate 3 Total weight 320 The procedure employed inpreparing a 320 mg. tablet was as follows:

2,3 dihydro-3-(N-methyl)carbamoyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine was mixed with the dicalcium phosphate, cornstarch and magnesium stearate in a suitable mixer. The mixture wasfurther blended by passing through a Fitzpatrick Comminuting Machinefitted with a No. 1A screen with knives forward. The mixed powders weresluggered on a table compressing machine. The slugs were comminuted to asuitable mesh side (No. 16 screen) '10 and mixed well. The tablets werecompressed at a tablet weight of 320 mg. using tablet punches having adiameter of (fiat beveled faced punches).

EXAMPLE 15 A capsule formulation Was prepared containing the followingingredients:

Amount per Ingredient: capsule, mg. 2,3-dihydro-3-(N-methyl)carbamoyl 7nitro- 5-phenyl-1H-1,4-bendodiazepine 50 Lactose, U.S.P. Corn starch,U.S.P. 30 Talc, U.S.P. 5

Total weight 210 A capsule formulation was prepared containing thefollowing ingredients:

Amount per Ingredient: capsule, mg.

2,3 dihydro-3-(N-methyl)carbamoyl 7 nitro-S-phenyl-lH-1,4-benzodiazepine25.5 Lactose 159.5 Corn starch 30.0

Talc 5.0

Total net weight 220.0

The procedure employed in preparing a capsule formulation was asfollows:

2,3-dihydro-3-(N-methyl)carbamoyl 7nitro-S-phenyl-1H-l,4-benz0diazepine, lactose and corn starch were mixedin a suitable mixer. The mixture was passed through a FitzpatrickComminuting Machine using a No. 1A screen and knives forward. Themixture was returned to the mixer and the talc added. It was blendedwell and filled into No. 4 two piece, hard gelatin capsules on a ParkeDavis capsulating machine. (Any similar type capsulating machine may beused.)

EXAMPLE 17 A suppository formulation was prepared containing thefollowing ingredients:

Amount per 1.3 gm.

Ingredient: suppository, gm.

2,3 dihydro-3-N-methyl)carbamoyl 7 nitro-S-phenyl-1H-1,4-benzodiazepine0.050 Wecobee M* 1.205 Carnauba wax 0.045

*Cocoa butter-coconut derived fat having a melting point of 96 F. to 98F. sold by E. F. Drew 00., New York, N.Y.

The procedure employed in preparing a suppository formulation was asfollows:

The Wecobee and the carnauba wax were melted in a suitable size glasslined container, mixed well and cooled to 45 C.2,3-dihydro-3-(N-methyl)carbamoyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine, which had been reduced to a fine powderwith no lumps, was added and stirred until completely and uniformlydispersed. The mixture was poured into suppository molds to yieldsuppositories having an individual weight of 1.3 gms. The suppositorieswere removed from molds and cooled. They were individually wrapped inwax paper for packaging.

1 1 EXAMPLE 18 A parenteral formulation was prepared containing thefollowing ingredients: Ingredient: Amount per ml.

2,3 clihydro 3(N-methyl)carbamoyl-7-nitro-S-phenyl-1H-1,4-benzodiazepine "mg" 5.0Propylene glycol ml 0.5 Benzyl alcohol (benzaldehyde free) ml 0.015Ethanol 95% U.S.P ml 0.10 Water for injection, q.s ml 1 The procedureemployed in preparing a parenteral formulation was as follows:

The 50 grams of 2,3-dihydro-3 -(N-methyl)carbamoyl-7-nitro-5-phenyl-1H-1,4-benz0diazepine were dissolved in a mixture of150 ml. of benzyl alcohol, 5000 ml. of propyleneglycol and 1000 ml. ofethanol. The solution was brought up to final volume of 10,000 ml. withwater for injection. The solution was filtered through an 02 Selascandle, filled into suitable size ampuls, gassed with nitrogen andsealed. It was then autoclaved at p.s.i. for minutes.

We claim: 1. A compound of the formula /NHQ R1 N02 ll ACHz-C-N wherein Ais selected from the group consisting of -('3=N and (|3HNH-acetyl}piperidine.

6. A compound of the formula:

n N0 A-CHg-C-N 12 wherein A is selected from the group consisting of Ris selected from the group consisting of hydrogen and lower alkyl;

R is selected from the group consisting of lower alkyl and hydrogen; andR and R taken together with their attached nitrogen atom form apyrrolidino or piperidino ring;

R is selected from the group consisting of phenyl, lower alkylsubstituted phenyl, halo substituted phenyl and pyridyl;

R6 is R, is hydrogen; and R and R taken together form the group R ishlydrogen or lower alkyl and R and R are lower a ky 7. The compound ofclaim 6 wherein said compound is 2[(2-formamido-S-nitrophenyl)phenylmethylenimino]- N-methylacetamide.

8. The compound of claim 6 wherein said compound is 2-[(2dimethylaminomethylenimino 5 nitrophenyl)- phenylmethyleneimino-N-methylacetamide.

9. The compound of claim 6 wherein said compound is 1-{2-[(2-acetamido 5nitrophenyl)-(2-chlorophenyl)- methylenimino]acetyl}piperidine.

10. The compound of claim 6 wherein said compound is 1-{2-[(2-acetamido5 nitrophenyl)phenylmethylenimin'o] acetyl}piperidine.

References Cited UNITED STATES PATENTS 3,370,091 2/1968 Archer et al260558 A OTHER REFERENCES C.A. 64: 15902-15903 (1966).

HENRY R. JILES, Primary Examiner S. D. WINTERS, Assistant Examiner US.Cl. X.R.

260293.77, 293.69, 295 AM, 326.5 E, 558A, 293.59

